Combination of brimonidine timolol for topical ophthalmic use

ABSTRACT

Disclosed are pharmaceutical compositions comprising brimondine and timolol for topical ophthalmic delivery and a method of treatment comprising administering said composition when indicated for glaucoma and associated conditions such as elevated intraocular pressure in the eyes of humans.

BACKGROUND OF THE INVENTION

This invention relates to the topical ophthalmic use of brimonidine in combination with timolol when indicated for treatment of glaucoma or ocular hypertension. Such combinations or formulations are available for separate use in the ophthalmic art and have been combined in serial application during the course of treatment of glaucoma. However, there are concerns and expressed reservations in the ophthalmic community about patient compliance when the patient is required to administer separate medications to treat a single disease or condition such as glaucoma. There is, moreover, a long felt need for an effective and safe topical ophthalmic pharmaceutical composition including brimonidine and timolol which has increased stability and requires a lower effective concentration of preservative as compared to the individual agents taken alone. Finally, there is a need to increase the efficacy of many topical ophthalmic agents, without increasing the systemic concentration of such topical agents, since it is well known that many of such topically-applied ophthalmic agents cause systemic side effects, e.g. drowsiness, heart effects, etc. Unexpectedly it has been discovered that brimonidine in combination with timolol meets these criteria.

Brimonidine is disclosed in U.S. Pat. No. 3,890,319. The use of brimonidine for providing neuroprotection to the eye is disclosed in U.S. Pat. Nos. 5,856,329; 6,194,415 and 6,248,741.

Timolol, as an ophthalmic drug, is disclosed in U.S. Pat. Nos. 4,195,085 and 4,861,760.

DESCRIPTION OF THE INVENTION

Brimonidine is an alpha adrenergic agonist represented by the following formula:

The chemical name for brimonidine is 5-Bromo-6-(2-imidazolidinylideneamino)quinoxaline L-tartrate.

Timolol is a beta adrenergic agent represented by the following formula:

Brimonidine is available from Allergan, Inc., Irvine, Calif. as an ophthalmic pharmaceutical product having the name Alphagan®. Timolol is available from various sources, including Merck Co., Rahway, N.J.

The compositions of the present invention are administered topically. The dosage is 0.001 to 1.0, e.g. mg/per eye BID; wherein the cited mass figures represent the sum of the two components, brimonidine and timolol. The compositions of the present invention can be administered as solutions in a suitable ophthalmic vehicle.

In forming compositions for topical administration, the mixtures are preferably formulated as 0.01 to 0.5 percent by weight brimonidine and 0.1 to 1.0 percent by weight timolol solution in water at a pH of 4.5 to 8.0, e.g. about 6.9. While the precise regimen is left to the discretion of the clinician, it is recommended that the solution be topically applied by placing one drop in each eye two times a day. Other ingredients which may be desirable to use in the ophthalmic preparations of the present invention include preservatives, co-solvents and viscosity building agents.

Antimicrobial Preservative:

Ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M, or other agents known to those skilled in the art. In the prior art ophthalmic products, typically such preservatives are employed at a level of from 0.004% to 0.02%. In the compositions of the present application the preservative, preferably benzalkonium chloride, may be employed at a level of from 0.001% to less than 0.01%, e.g. from 0.001% to 0.008%, preferably about 0.005% by weight. It has been found that a concentration of benzalkonium chloride of 0.005% is sufficient to preserve the compositions of the present invention from microbial attack. This concentration may be advantageously compared to the requirement of 0.01% benzalkonium chloride to preserve timolol in the individual, commercially-available ophthalmic products. Moreover, it has been found that adequate lowering of intraocular pressure has been obtained when administering the compositions of this invention twice a day as compared to the FDA-approved regimen wherein brimonidine ophthalmic solution, i.e. Alphagan® ophthalmic solution is administered three times a day and timolol ophthalmic solution, i.e. Timoptic® ophthalmic solution is administered twice a day. This results in the exposure of the patient to 67% and 50% of benzalkonium chloride, with the compositions of this invention, as compared to the administration of Alphagan® and Timoptic®, respectively. In FDA-approved adjunctive therapy, wherein Alphagan® and Timoptic® are serially administered, the patient is exposed to almost three times the concentration of benzalkonium chloride as compared to the administration of the compositions of this invention twice a day. (It is noted that it is known that benzalkonium chloride at high concentrations is cytotoxic. Therefore, minimizing the patient's exposure to benzalkonium chloride, while providing the preservative effects afforded by benzalkonium chloride, is clearly desirable.) Co-Solvents:

The solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition. Such cosolvents include polysorbate 20, 60, and 80, Pluronic F68, F-84 and P-103, cyclodextrin, or other agents known to those skilled in the art. Typically such co-solvents are employed at a level of from 0.01% to 2% by weight.

Viscosity Agents:

Viscosity increased above that of simple aqueous solutions may be desirable to increase ocular absorption of the active compound, to decrease variability in dispensing the formulation, to decrease physical separation of components of a suspension or emulsion of the formulation and/or to otherwise improve the ophthalmic formulation. Such viscosity building agents include as examples polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of from 0.01% to 2% by weight.

The present invention further comprises an article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for lowering intraocular pressure and wherein the packaging material comprises a label which indicates the pharmaceutical agent can be used for lowering intraocular pressure and wherein said pharmaceutical agent comprises an effective amount of brimonidine and an effective amount of timolol.

The following example is a representative pharmaceutical composition of the invention for topical use when indicated for treating glaucoma.

EXAMPLE I

The combination of active pharmaceutical ingredients is as follows:

-   Brimonidine Tartrate 0.20% (w/v) and Timolol Maleate 0.68% (w/v)     (Equivalent to 0.50% (w/v) timolol)

The Brimonidine-Timolol combination formulation presented in the Table, below, is a sterile, preserved, aqueous solution. The formulation vehicle is based upon a timolol ophthalmic solution which contains an isotonic phosphate buffer system at pH 6.9. The formulation preservative is benzalalkonium chloride (BAK) at a concentration of 0.005% (w/v) (50 ppm). The formulation passes regulatory required preservative efficacy testing (PET) criteria for USP (United States Pharmacopoeia) and EP (European Pharmacopoeia-A and -B over 24 months.

TABLE Ingredient Function Concentration, % (w/v) Brimonidine Tartrate Active 0.2 Timolol Maleate, EP Active 0.68¹ Benzalkonium Chloride, NF, EP Preservative 0.005 Sodium Phosphate, monobasic Buffer 0.43 monohydrate, USP Sodium Phosphate, dibasic Buffer 2.15 heptahydrate, USP Sodium Hydroxide, NF pH adjust Adjust pH to 6.9 Hydrochloric Acid, NF pH adjust Adjust pH to 6.9 Purified Water, USP, EP Solvent q.s. ad ¹Equivalent to 0.5% (w/v) Timolol, free base

The pharmaceutical composition of Example I is used in the clinical study reported below.

EXAMPLE II

Objectives:

-   To compare the safety and efficacy of twice-daily dosed brimonidine     tartrate 0.2%/timolol 0.5% ophthalmic solution combination     (henceforth referred to as Combination) with that of twice-daily     dosed timolol ophthalmic solution 0.5% (henceforth referred to as     Timolol) and three-times-daily dosed ALPHAGAN® (brimonidine tartrate     ophthalmic solution) 0.2% (henceforth referred to as Brimonidine)     administered for three months plus 9-month masked extension) in     patients with glaucoma or ocular hypertension.     Methodology: -   Structure: multicenter, double-masked, randomized, parallel-group,     active control -   Randomization: patients were randomized to one of the 3 masked     treatment groups (Combination, Brimonidine or Timolol) based on an     even allocation at each site -   Visit Schedule: prestudy, baseline (day 0), week 2, week 6, month 3,     month 6, month 9, and month 12     Number of Patients (Planned and Analyzed): -   560 planned to enroll; 586 enrolled (Combination=193,     Brimonidine=196, Timolol=197); 502 completed. Mean (range) age: 62.4     (23 to 87) years; 46.1% (270/586) males, 53.9% (316/586) females.     Diagnosis and Main Criteria for Inclusion: -   Diagnosis: ocular hypertension, chronic open-angle glaucoma, chronic     angle-closure glaucoma with patent iridotomy, pseudoexfoliative     glaucoma or pigmentary glaucoma and requiring bilateral treatment. -   Key Inclusion Criteria: ≧18 years, day 0 (post-washout) intraocular     pressure (IOP) ≧22 mm Hg and ≦34 mm Hg in each eye and asymmetry of     IOP≦5 mm Hg, best-corrected Early Treatment of Diabetic Retinopathy     Study (ETDRS) visual acuity equivalent to a Snellen score of 20/100     or better in each eye. -   Key Exclusion Criteria: uncontrolled systemic disease, abnormally     low or high blood pressure or pulse rate for age or contraindication     to beta-adrenoceptor antagonist therapy, anticipated alteration of     existing chronic therapy with agents which could have a substantial     effect on IOP, contraindication to brimonidine therapy, allergy or     sensitivity to any of the study medication ingredients, anticipated     wearing of contact lenses during the study, laser surgery,     intraocular filtering surgery or any other ocular surgery within the     past 3 months, or required chronic use of other ocular medications     during the study (intermittent use of artificial tear product was     allowed).     Test Product, Dose and Mode of Administration, Batch Number: -   Brimonidine tartrate 0.2%/timolol 0.5% combination ophthalmic     solution one drop (˜35 μL) instilled in each eye BID in the morning     and evening; and vehicle of the Combination ophthalmic solution, one     drop (˜35 μL) instilled in each eye once daily (QD) in the afternoon     (for masking purposes). -   Duration of Treatment: 3 months (with a 9-month Masked Extension)     Reference Therapy, Dose and Mode of Administration, Batch Number: -   Active control ALPHAGAN® (brimonidine tartrate ophthalmic solution)     0.2%, one drop (˜35 μL) instilled in each eye TID in the morning,     afternoon, and evening. Active control timolol ophthalmic solution     0.5%, one drop (˜35 μL) instilled in each eye BID in the morning and     evening; and vehicle of the Combination ophthalmic solution, one     drop (˜35 μL) instilled in each eye once daily (QD) in the afternoon     (for masking purposes).     Criteria for Evaluation: -   Efficacy: -   IOP (hours 0, 2, 7, and 9), patient satisfaction questionnaire,     patient comfort of study medication questionnaire, pharmacoeconomic     evaluation by investigator -   Safety: -   Adverse events (AE), biomicroscopy, visual acuity (VA), visual     field, ophthalmoscopy, cup/disc ratio, heart rate, blood pressure,     hematology, serum chemistry, urinalysis and pregnancy test. -   Other: -   Quantitation of plasma brimonidine and timolol concentrations (at     selected sites), resource utilization (to be reported upon     completion of the 1 year study).     Statistical Methods: -   All data were summarized with descriptive statistics, frequency     tables, and/or data listings. Safety analyses included all patients     who received at least 1 dose of study medication. Analyses were     performed for the primary efficacy variable IOP using the     intent-to-treat (ITT) population with last observation carried     forward (LOCF), and the per protocol population with observed cases. -   Ordinal categorical variables were analyzed by the Wilcoxon rank-sum     test. Nominal categorical variables were analyzed using Fisher's     exact or Pearson's chi-square tests. Within-group changes from     baseline for categorical variables were analyzed using the Wilcoxon     signed-rank test. Continuous variables (eg, IOP) were analyzed using     analysis of variance (ANOVA). Within-group changes from baseline for     continuous variables were analyzed using paired t-tests. -   A 2-way ANOVA model with factors for treatment and investigator was     used for the analysis of IOP. Comparisons were made between the     Combination and each of the 2 monotherapies in a pairwise fashion     using contrasts from the ANOVA model, with the same error term. A     separate ANOVA model was employed at each hour/visit measurement of     IOP. Each of the 2 null hypotheses (Combination versus Timolol and     Combination versus Brimonidine) was tested at the 0.05 significance     level. Point estimates of the mean treatment differences, as well as     2-sided 95% confidence intervals (CI) of the difference, were     provided at each timepoint.     Summary—Conclusions -   Efficacy:

At baseline, mean values of diurnal IOP ranged from 22.2 mm Hg to 24.9 mm Hg in the Combination group, 22.5 mm Hg to 25.0 mm Hg in the Brimonidine group, and 22.3 mm Hg to 24.8 mm Hg in the Timolol group. There were no statistically significant differences between treatment groups.

-   Mean changes from baseline diurnal IOP at week 2, week 6 and month 3     ranged from:     -   −5.2 to −7.9 mm Hg in the Combination group     -   −3.5 to −5.7 mm Hg in the Brimonidine group     -   −4.5 to −6.4 mm Hg in the Timolol group -   The mean decreases from baseline diurnal IOP were statistically     significant within each treatment group at each follow-up timepoint     (p<0.001). -   The mean decrease from baseline diurnal IOP was statistically     significantly greater with Combination than with Brimonidine at     hours 0, 2, and 7 at all follow-up visits (p<0.001). In addition,     clinically significant differences of more than 1.5 mm Hg in mean     change from baseline IOP favoring Combination over Brimonidine were     seen at hours 0, 2, and 7 at all follow-up visits. At hour 9, the     decreases from baseline diurnal IOP were greater for the Combination     group than the Brimonidine group at all follow-up visits, although     the differences were not statistically significant (p≧0.104). -   The mean decrease from baseline diurnal IOP was statistically     significantly greater with Combination than with Timolol at hours 0,     2, 7 and 9 at all follow-up visits (p≦0.041). In addition,     clinically significant differences of more than 1.5 mm Hg in mean     change from baseline IOP favoring Combination over Timolol were seen     at week 2 (hours 0, 2, and 7), week 6 (hours 2 and 7), and month 3     (hours 0 and 2). -   Mean values of diurnal IOP at week 2, week 6 and month 3 ranged     from:     -   15.9 to 18.1 mm Hg in the Combination group     -   17.4 to 21.5 mm Hg in the Brimonidine group     -   17.5 to 18.9 mm Hg in the Timolol group -   Mean values of diurnal IOP were statistically significantly less     with Combination than with Brimonidine at hours 0, 2, and 7 at all     follow-up visits (p<0.001) and at hour 9 at week 6 and month 3     (p≦0.011). The mean values of IOP at hour 9 at week 2 were lower for     the Combination group than the Brimonidine group, although the     difference was not statistically significant (p=0.205). In addition,     clinically significant differences of more than 1.5 mm Hg in mean     IOP favoring Combination over Brimonidine were seen at hours 0, 2,     and 7 at all follow-up visits and at hour 9 at month 3. -   Mean values of diurnal IOP were statistically significantly less     with Combination than with Timolol at hour 0 at week 2 and month 3;     and at hours 2, 7 and 9 at all follow-up visits (p≦0.050). The mean     values of IOP at hour 0, week 6, were lower for the Combination     group than the Timolol group, although the difference was not     statistically significant (p=0.102). In addition, clinically     significant differences of more than 1.5 mm Hg in mean IOP favoring     Combination over Timolol were seen at week 2 (hours 0, 2, and 7),     week 6 (hours 2, 7, and 9), and month 3 (hours 2 and 9). -   At the month 3 or exit visit, a statistically significantly greater     “yes” response to the Investigator Pharmacoeconomic Evaluation was     recorded for patients receiving Combination (91.1%, 173/190) than     for patients receiving Brimonidine (73.4%, 141/192, p<0.001). A     “yes” response was recorded for 92.7% (179/193) of patients     receiving Timolol. There were no statistically significant     differences in the change from baseline in treatment comfort between     Combination and each of the monotherapy groups. -   Treatment satisfaction was better than baseline for a statistically     significantly greater percentage of patients in the Combination     group (23.4%, 36/154) than in the Brimonidine group (13.2%, 20/151,     p=0.005). A total of 19.9% (30/151) of patients in the Timolol group     reported better treatment satisfaction than baseline.     Safety: -   Through month 3 of the study, 53.4% (103/193) of patients in the     Combination group, 61.7% (121/196) of the Brimonidine group, and     50.8% (100/197) of the Timolol group experienced one or more adverse     events, regardless of causality. The incidences of oral dryness, eye     pruritus, foreign body sensation and conjunctival folliculosis were     statistically significantly lower with the Combination than with     Brimonidine (p≦0.034), while burning and stinging were statistically     significantly higher with the Combination than with Brimonidine     (p≦0.028). There were no statistically significant differences in     adverse events between the Combination and Timolol, except for a     statistically significantly higher incidence of eye discharge with     the Combination (2.6%, 5/193) compared to Timolol (0%, 0/197;     p=0.029). The most frequently reported adverse events (>3% in any     treatment group) were as follows, tabulated by descending order in     the Combination group:

Combination Brimonidine Timolol Preferred Term N = 193 N = 196 N = 197 burning sensation in eye 23 (11.9%) 11 (5.6%) 25 (12.7%) conjunctival hyperemia 16 (8.3%) 23 (11.7%) 11 (5.6%) stinging sensation eye 13 (6.7%)  4 (2.0%) 11 (5.6%) infection (body as a 11 (5.7%)  6 (3.1%)  8 (4.1%) whole) visual disturbance  6 (3.1%) 11 (5.6%)  3 (1.5%) epiphora  5 (2.6%)  8 (4.1%)  3 (1.5%) oral dryness  4 (2.1%) 19 (9.7%)  1 (0.5%) eye pruritus  3 (1.6%) 13 (6.6%)  3 (1.5%) allergic conjunctivitis  3 (1.6%)  7 (3.6%)  0 (0.0%) asthenia  3 (1.6%)  6 (3.1%)  1 (0.5%) foreign body sensation  2 (1.0%) 10 (5.1%)  5 (2.5%) conjunctival folliculosis  2 (1.0%)  9 (4.6%)  1 (0.5%) somnolence  2 (1.0%)  7 (3.6%)  0 (0.0%)

-   Adverse events led to the discontinuation of 3.6% (7/193) of     patients in the Combination group, similar to 3.0% (6/197) of     patients in the Timolol group, and statistically significantly less     than 14.3% (28/196) of patients in the Brimonidine group (p<0.001).     Serious adverse events were reported for 1.0% (2/193) of patients in     the Combination group, 2.0% (4/196) of patients in the Brimonidine     group, and 2.0% (4/197) of patients in the Timolol group. Two     patients receiving Timolol had 4 serious adverse events (emphysema     in one patient; nausea, sweating, and tachycardia in the other     patient) which were considered possibly related to the study drug.     There was 1 death in the Brimonidine group, possibly due to     complications from cardiac surgery, and not related to study drug. -   There were no clinically relevant differences between the     Combination and either of the individual components in the mean     change from baseline to month 3 for any hematology, chemistry, or     urinalysis parameter. Statistically significant (p≦0.048)     within-group changes from baseline were found, but were small and     not clinically relevant. -   Small but statistically significant (p≦0.001) mean reductions in     heart rate ranging from −2.1 to −3.7 bpm were seen with the     Combination, similar to Timolol. Small but statistically significant     (p≦0.003) mean reductions in blood pressure at hour 2 (postdose)     were seen with the Combination, similar to Brimonidine. These small     changes in mean heart rate and blood pressure were associated with     clinical symptoms in only a few patients. -   Increases from baseline in the severity of conjunctival erythema and     conjunctival follicles on biomicroscopy were statistically     significantly less with the Combination than with Brimonidine     (p≦0.011). The majority of patients in each treatment group showed     less than a 2-line change from baseline visual acuity. There were no     significant between-group differences for changes in visual fields     or cup/disc ratio.     Pharmacokinetics: -   Blood samples were available for 55 patients in the Combination     group, 49 patients in the Brimonidine group, and 54 patients in the     Timolol group. All samples were assayed for both brimonidine (lower     limit of quantitation [LLOQ] 5 pg/mL) and timolol (LLOQ 5 pg/mL).     Plasma brimonidine and timolol concentrations were not quantifiable     in all but 1 sample on day 0, hour 0 for both Combination and the     monotherapy treatment groups. -   In the Combination group, mean±standard deviation (SD) plasma     brimonidine concentrations 1 hour postdose at week 2 and month 3     were 49.7±36.1 and 52.8±46.7 pg/mL, respectively. In the Brimonidine     group, mean±SD plasma brimonidine concentrations at week 2 and month     3 were 81.0±63.8 and 78.6±48.9 pg/mL, respectively. In the     Combination group, mean±SD plasma timolol concentrations at week 2     and month 3 were 0.499±0.327 and 0.586±0.580 ng/mL, respectively. In     the Timolol group, mean±SD plasma timolol concentrations at week 2     and month 3 were 0.950±0.709 and 0.873±0.516 ng/mL, respectively. -   Plasma brimonidine and timolol concentrations 1 hour postdose were     steady and did not increase over the 3-month study duration.     Brimonidine concentrations were 39%, 34% and 39% lower in the     Combination group than in the monotherapy group at week 2 (p=0.004),     month 3 (p=0.013), and month 12, respectively. Timolol     concentrations were 47% and 33% lower in the Combination group than     in the monotherapy group at week 2 (p<0.001) and month 3 (p=0.011),     respectively. -   Timolol concentrations were also significantly lower in the     combination treatment group than in the Timolol monotherapy     treatment group (p=0.0006). Timolol concentrations were 49%, 32%,     and 21% lower in the combination group than in the monotherapy group     at week 2, month 3, and month 12, respectively. -   The plasma brimonidine concentration in males was statistically     significantly lower than in females for the Brimonidine group (37%     lower at week 2 [p=0.034] and 37% lower at month 3 [p=0.017]); the     difference was not statistically significant in the Combination     group. The plasma timolol concentration in males was statistically     significantly lower than in females for both the Combination group     (not statistically significant at week 2; 52% lower at month 3     [p=0.012]) and the Timolol group (45% lower at week 2 [p=0.006] and     39% lower at month 3 [p=0.003]). -   Plasma brimonidine concentration in the elderly group was not     significantly different from in the young group for the combined     data from both the combination and Brimonidine treatment groups     (p-value=0.1323). However, plasma timolol concentration in the young     group was significantly lower than in the elderly group for combined     data from both the combination and the Timolol treatment groups     (p-value=0.0005).     Conclusions: -   The Combination treatment (brimonidine tartrate 0.2%/timolol 0.5%)     administered BID for 3 months was superior to Timolol (timolol 0.5%)     BID and Brimonidine (brimonidine tartrate 0.2%) TID in lowering the     elevated IOP of patients with glaucoma or ocular hypertension. The     Combination administered BID demonstrated a favorable safety profile     that was comparable to Timolol BID and better than Brimonidine TID     with regard to the incidence of adverse events and discontinuations     due to adverse events.

The invention has been described herein by reference to certain preferred embodiments. However, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto. 

1. A method of treating glaucoma or ocular hypertension by topical administration of about 0.2% brimonidine by weight to an eye of a person in need thereof, said improvement comprising topically administering to said eye, in a single composition, about 0.2% brimonidine by weight and about 0.5% timolol by weight twice a day; as the sole active agents; wherein said method is as effective as administration of 0.5% timolol twice a day and 0.2% brimonidine three times a day to said eye, wherein the two compounds are administered in separate compositions.
 2. The method of claim 1 wherein said composition further comprises from 0.001% to 0.01% benzalkonium chloride.
 3. The method of claim 2 wherein said composition comprises about 0.005% benzalkonium chloride.
 4. A method of reducing the number of daily topical ophthalmic doses of brimondine administered topically to an eye of a person in need thereof for the treatment of glaucoma or ocular hypertension from 3 to 2 times a day without loss of efficacy, wherein the concentration of brimonidine is 0.2% by weight, said method comprising administering said 0.2% brimonidine by weight and 0.5% timolol by weight in a single composition. 